V2i / 20A09 / 16B16: Outline the influence of pregnancy on pharmacokinetics

20A09: Exam Report

Outline the changes to drug pharmacokinetics and pharmacodynamics that occur at term in pregnancy

7% of candidates passed this question.

Answers framed around absorption, distribution, metabolism and excretion performed better.

Some brief comments on physiology are required as the basis for pharmacokinetic change, but discussion of physiology that was not then specifically related to pharmacology did not score marks.

Specific ‘real life’ examples necessitating change in practice or prescribing were well regarded e.g. reduction in spinal/epidural local anaesthetic dosing.

Vague statements about possible or theoretical changes were less well regarded.

16B16: Exam Report

Outline the influence of pregnancy on pharmacokinetics.

47% of candidates passed this question.

Most candidates divided the answer into effects on absorption, distribution, metabolism and elimination, which is a good way of presenting the answer. However, the good candidates also mentioned effects on the foetus due to ion trapping caused by the more acidic foetal blood.

Many candidates forgot to include effect on epidural administration of drugs in pregnancy caused by engorged epidural veins during labour.

Candidates lost marks for omitting the effect of increased cardiac output on the rate of distribution of IV drugs to effector sites, the effect of increased hepatic blood flow on drugs with high intrinsic clearance, the increased clearance of drugs with renal clearance due to increased GFR & renal plasma flow.

V2i / 20A09 / 16B16: Outline the influence of pregnancy on pharmacokinetics

Definition

Full term in pregnancy is 39 0/7 – 40 6/7 weeks of gestation

PK & PD is affected by the CVS, Resp, Renal, GI and Haem physiological changes in pregnancy

PK

Absorption

Changes in Pregnancy

Mechanism

Clinical Effect

Decreased GI motility

Decreased gastric emptying

Progesterone

Gravid Uterus

Labour

↓oral absorption

­↑oral absorption acidic drugs in stomach

Vomiting

Uncertain mechanism

?bHCG ?GI dysmotility

↓oral absorption

­↑RR↑­Vt ↑­MV

↓FRC

Progesterone

Gravid uterus

­↑rate volatile absorption

­↑CO

Progesterone →Na+ loss →RAAS activation →volume expansion

↓arm-brain-circulation time →faster IV onset

Faster onset IM/sc/topical

Epidural vein engorgement

­↑CO & VD

↑­rate absorption epidural meds, decreased volume required

Distribution

Changes in Pregnancy

Mechanism

Clinical Effect

­TBW

­RAAS & Body fat stores

­↑Vd – especially hydrophilic drugs (ie NDMR) require larger doses, esp for loading

↑­fat stores

Multiple hormonal

­Vd lipophilic drugs, possibly longer CSHT

↓Albumin

Dilutional

↑­unbound fraction of highly PPB drugs; midazolam, digoxin, phenytoin, Vaproic acid

Resp Alkalosis

Progesterone →↑­MV

­ ↑unionised basic drugs

↓unionised acidic drugs

Foetal distribution

Placental circulation

Fetal pH 0.1 less than maternal

­ ↑­Vd lipophilic drugs

Ion trapping, esp of basic drugs in acidic pH

Metabolism

Changes in Pregnancy

Mechanism

Clinical Effect

Slight ↑/no change Hepatic BF

↑­CO

­ ↑­­metabolism drugs with High ER

Lower PPB

dilution

Increased available for metabolism/elim

Hepatic enz induction / inhibition

P induces

O inhibits

Depending on P:O ration,

Induction = ­↑metab

Inhibition = ↓metab

Eg

CYP2D6 induced during pregnancy

  • Rapid metaboliseres of prodrug codeine will have high plasma peaks of morphine wh will be transferred to breast milk
  • ↑­metabolism of metoprolol = ↓bioavailability and ↓plasma levels

 

CYP3A induction = ­↑Metabolism of Midazolam = ↓plasma concentration

↓Plasma  Cholinesterase (30%)

No issue for SUX, balanced by ­↓Vd

Elimination

Changes in Pregnancy

Mechanism

Clinical Effect

­↑GFR

­↑CO →↑­RBF

↑­renal drug clearance (esp hydrophilic)

­↑­MV

P

↑­volatile washout 

PD

Neurological

  • Increased sensitivity to volatiles (decreased MAC)
  • Increased sensitivity to IV hypnotics
  • Increased sensitivity to local anaesthetics
  • Duration of anaesthesia before delivery should be kept as low as possible to prevent drug contamination of fetus

Cardiovascular

  • Ephedrine has more favourable profile cf metaraminol which reduces Uterine BF

Gastrointestinal

  • Increased O = increase cholesterol, fibrinogen and clotting
  • ALKP elevated as it’s produced by placenta

Haematological

  • Hypercoagulable state due to blood stasis and increase in clotting factors, fibrinogen and vWF
  • Heparin does not cross placenta

Endocrine

  • Plasma Iodide levels falls due to increased maternal clearance
  • Increased levthoyroxine dose in pregnancy

ID

  • Penicillins are safe and often need dose increase due to increased renal clearance
  • Cephalosporins: increased dosing of gen 1 & 2, unchanged gen 3 dosing

DRUG CLASSES: most medications cross placenta and therefore all drugs are categorised according to their safety profile.  Each drug should be checked prior to administration